The present invention relates to 4xe2x80x2-methanesulfonyl-biphenyl derivatives as a highly selective cyclooxygenase-2 inhibitor.
Most of non-steroid anti-inflammatory drugs represent actions such as anti-inflammation, analgesic, and antipyretic activity by inhibiting the enzymatic activity of cyclooxygenase or prostaglandin G/H synthase. In addition, they can suppress the uterine contraction induced by hormones and the cell proliferation in several kinds of cancers. First, only cyclooxygenase-1 was known to be found in cow as a constitutional enzyme. But recently, cyclooxygenase-2 is elucidated as an induced form. Cyclooxygenase-2 is identified to be discriminated clearly from cyclooxygenase-1 and can be provoked easily by mitogen, endotoxin, hormones, growth factors, cytokines and the like.
Prostaglandins have various pathological and physiological functions. Precisely, cyclooxygenase-1 as a constitutional enzyme participates in the secretion of basic endogenous prostaglandin and plays an important role in physiological aspects such as stomach homeostasis, renal blood circulation and so on. On the other hand, cyclooxygenase-2 is induced by inflammatory factors, hormones, growth factors, cytokines and the like and thus plays an important role in pathological effects of prostaglandins. Therefore, selective inhibitors against cyclooxygenase-2 are expected to have no side effect on account of the functional mechanism compared with the anti-inflammatory drugs such as conventional non-steroid agents and to represent actions such as anti-inflammation, analgesic, and antipyretic activity. Furthermore, it is estimated to suppress the uterine contraction induced by hormones and the cell proliferation in several kinds of cancers. Especially, it probably has less side effects such as gastrointestinal toxicity, renal toxicity and the like. Also, it is assumed to prevent the synthesis of contractive prostanoids and thus inhibit the contraction of smooth muscle induced by the prostanoid. Hence, it can be applied usefully to treat a premature birth, dysmenorrhea, asthma and several diseases associated with eosinophilic leukocytes. Besides, it can be exploited widely to cure osteoporosis, glaucoma and athymia, which has been disclosed in a lot of references, especially the usefulness of selective inhibitors against cyclooxygenase-2 (References: John Vane, xe2x80x9cTowards a better aspirinxe2x80x9d in Nature, Vol. 367, pp 215-216, 1994; Bruno Battistini, Regina Botting and Y. S. Bakhle, xe2x80x9cCOX-1 and COX-2; Toward the Development of More Selective NSAIDsxe2x80x9d in Drug News and Perspectives, Vol. 7, pp 501-512, 1994; David B. Reitz and Karen Seibert, xe2x80x9cSelective Cyclooxygenase Inhibitorsxe2x80x9d in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, pp 179-188, 1995).
The selective inhibitors against cyclooxygenase-2 have been reported to have various structural forms. Among these, the diaryl heterocycle structure, namely a tricyclic system, has been studied most frequently and exploited to construct a lot of candidate substances. In this structure, it is essential that sulfonamide or methanesulfone group exist onto one phenyl group. The initial substance of such a structure is identified to be Dup697 (Bioorganic and Medicinal Chemistry Letters, Vol. 5, No. 18, p 2123, 1995). Then, as a derivative, SC-58635 (Journal of Medicinal Chemistry, Vol. 40, p 1347, 1997) having a pyrrazole structure, MK-966 (WO 95/00501) having a furanone structure and the like are disclosed.
Based upon the above technical backgrounds, the inventors of the present invention have tried a lot in order to develop novel compounds as a highly selective cyclooxygenase-2 inhibitor. As a result, we have found that 4xe2x80x2-methanesulfonyl-biphenyl derivatives of formula 1 satisfied such a purpose and completed the present invention successfully.
Therefore, the object of the present invention is to provide 4xe2x80x2-methanesulfonyl-biphenyl derivatives of formula 1 and its pharmaceutically acceptable salts as depicted below.
Hereinafter, the present invention will be described more clearly.
The present invention relates to 4xe2x80x2-methanesulfonyl-biphenyl derivatives of formula 1 and its pharmaceutically acceptable salts.
 less than Formula 1 greater than 
Wherein, R1 and R2 are respectively a hydrogen;
C1-C4-alkyl substituted or not substituted by halogens;
C3-C7-cycloalkyl;
C1-C5-alkyl containing 1xcx9c3 ether bonds and/or an aryl substitute;
substituted or not substituted phenyl;
or substituted or not substituted five or six ring-cycled heteroaryl containing more than one hetero atoms selected from a group consisting of nitrogen, sulfur and oxygen (wherein, phenyl or heteroaryl can be one- or multi-substituted by a substituent selected from a group consisting of hydrogen, methyl, ethyl and isopropyl).
The compound of the present invention can exist as a pharmaceutically acceptable salt form, wherein the pharmaceutically acceptable salt means a nontoxic salt containing organic salt and inorganic salt and accepted pharmaceutically. The inorganic salt consists of aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc and the like and preferably, ammonium, calcium, magnesium, potassium, sodium. The organic salt consists of primary-, secondary- or tertiary-amines, naturally substituted amines, cyclic amines, modified salts prepared through basic ion exchange resin and the like. Preferably, the organic salt can be selected among arginine, betain, caffeine, colin, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholin, N-ethylpiperidine, N-methylglucamine, glucamine, glucosamine, histidine, hydrapamine, N-(2-hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine, morpholin, piperazine, piperidine, polyamine resin, procain, purine, teobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Besides, the compound of the present invention can be a salt form of nontoxic acids containing the organic acid and the inorganic acid and accepted pharmaceutically, in case that it be basic. Preferably, the acid can be adopted among acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzenesufonic acid, benzo acid, camposulfonic acid, citric acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, ethylendiaminetetraacetic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydriodic acid, hydrobromic acid, hydrochloric acid, icethionic acid, lactic acid, maleic acid, malic acid, manderic acid, methanesulfonic acid, music acid, 2-naphthalene disulfonic acid, nitric acid, oxalic acid, parnoic acid, pantothenic acid, phosphoric acid, pivalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, 10-undecenoic acid and the like and more preferably, among succinic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, phosphoric acid, sulfuric acid, tartaric acid and the like.
Preferably, the compound of the present invention of formula 1 as a selective inhibitor against cyclooxygenase-2 is that R1 and R2 are separately methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclopentyl, or benzyl.
For preferred embodiments of the present invention, the compounds of formula 1 will be described more clearly as follows:
4xe2x80x2-methanesulfonyl-3,4-dimethoxy-biphenyl;
4xe2x80x2-methanesulfonyl-3,4-diethoxy-biphenyl;
4xe2x80x2-methanesulfonyl-3,4-dipropyloxy-biphenyl;
4xe2x80x2-methanesulfonyl-3,4-diisopropyloxy-biphenyl;
4xe2x80x2-methanesulfonyl-3,4-dicyclopropyloxy-biphenyl;
4xe2x80x2-methanesulfonyl-3,4-dibutyloxy-biphenyl;
4xe2x80x2-methanesulfonyl-3,4-dibenzyloxy-biphenyl;
4xe2x80x2-methanesulfonyl-3,4-dicyclopentyloxy-biphenyl; and
3-butoxy-4-isopropoxy-4xe2x80x2-methanesulfonyl-biphenyl
On the other hand, the compounds of formula 1 in the present invention can be prepared by performing the procedures as illustrated below.
However, the process for preparing the compounds of the present invention will not be restricted to following descriptions, especially in reaction solvents, bases, amounts of used reactants and the like.
Moreover, the compound of the present invention also can be prepared by exploiting and combining various synthetic methods described in the present specification or disclosed in other references of those skilled in this arts with a coordinate and arbitrary mode.
Those skilled in the art will appreciate that the conceptions and specific embodiments disclosed in the foregoing description may be readily utilized as a basis for modifying or designing other embodiments.
Concretely, the compound of formula 1 in the present invention can be prepared by exploiting cathechol as an initial material as illustrated schematically in following reaction formula 1 and 2.
 less than Reaction Formula 1 greater than 
Wherein, R signifies R1 and R2, Formula (1a) represents that R1 and R2 are identical in the compound of formula 1.
In the process for the preparation of the present invention, it is most important to prepare a biphenyl intermediate through the Suzuki reaction after adopting a selective protecting group to cathechol, an initial substance.
In the process for adopting a selective protecting group to cathechol, an initial substance, the reaction solvent can be an organic solvent commonly used such as dichloromethane, chloroform, tetrahydrofurane, dimethylformamide, benzene, toluene, diethylether and the like and dimethylformamide is the most preferable among these. Tetrahydrofurane and diethylether are recommended to exploit with purifying. Resulting intermediate compound should be selectively brominated at the range of 0xcx9cxe2x88x9280xc2x0 C. and more preferably, at a low temperature in between xe2x88x9275xcx9cxe2x88x9280xc2x0 C. Catalyst which is used in Suzuki reaction to form biphenyl derivatives can be selected among palladiumacetate, tetrakistriphenylphosphinepalladium, and bistriphenylphosphinepalladium chloride and tetrakistriphenylphosphinepalladium is most preferable. The reaction should be progressed under the presence of inorganic salt group such as sodiumacetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like and potassium carbonate is most preferable among these. Additionally, benzene, tetrahydrofuran, toluene, dimethylformamide and the like are utilized as a solvent and benzene and toluene are most preferable. Oxidizing agent which is utilized in a process of oxidizing sulfanyl group included in biphenyl intermediate into sulfonyl group is mainly selected from OXONE, hydrogen peroxide, magnesium monoperoxyphthalate hexahydrate, metachloroperoxybenzoic acid and the like. There is no problem to exploit anything among these, but magnesium monoperoxyphthalate hexahydrate is most preferable.
In reaction formula 1, R1 group is adopted to 4-location of biphenyl first, and then pivaloyl group to 3-location as a protecting group. In this case, pivaloyl group is seceded in the process of hydrolyzing methanesulfonyl group which has been formed onto 4xe2x80x2-location of biphenyl and then, R2 group is adopted to 3-location of biphenyl. As a result, the compound of formula 1 where R1 and R2 are mutually different is obtained.
In reaction formula 2, t-butyldimethylsilyl group is adopted to 4-location of biphenyl as a protecting group and pivaloyl group to 3-location as a protecting group. In this case, both t-butyldimethylsilyl group and pivaloyl group are seceded in the process of hydrolyzing methanesulfonyl group which has been formed onto 4xe2x80x2-location of biphenyl and then, diol compound is formed. By reacting diol compound with Rx compound, a compound where R1 and R2 are identical is obtained.
After completing the reaction, the resulting products can be processed through a common treatment such as chromatography, re-crytallization and the like so as to be separated and purified.
The compound of the present invention depicted in formula 1 has an activity for the selective inhibition against cyclooxygenase-2 and thus can be utilized as an enzymatic inhibitor. The compound of formula 1 as a selective inhibitor against cyclooxygenase-2 can be a substitute for conventional non-steroid anti-inflammatory drugs. Concretely, it improves side effects of anti-inflammatory drugs in existed non-steroids and is useful in patients suffering from peptic ulcer, gastritis, partial enteritis, ulcerative colitis, diverticulitis, gastrointestinal haemorrhagia, hypoprothrombinemia and the like. Besides, it is expected to treat inflammatory diseases such as osteoarthritis, rheumatoid arthritis and the like effectively.
The compound of the present invention can be administered in a single dose or in separated doses, depending upon clinical purposes. The specific dosage for patients will vary, depending upon factors such as a sort of drug compound, body weight, sex, physical condition, diet, administration period, administration method, discharge ratio, drug composition and severity of diseases and the like.
The compound of the present invention can be administered as an oral, a local, a parenteral (subcutaneous, venous and muscular syringe or injection), an inhalational or a rectal drug. In case that these are prepared to a pharmaceutical drug, one or more commonly used vehicles, methods for the preparation and the like can be adopted properly from prior arts widely reported to those skilled.
In order to attain the desired purpose of clinical administration, the active compound of formula 1 in the present invention can be administered coincidently by combining more than one component of other commercial drugs.
However, the pharmaceutical drugs containing the compound of the present invention is not limited to forms described above, if it has a purpose for inhibiting cyclooxygenase-2 selectively. All kinds of drugs useful for the enzymatic inhibition can be within the scope of the present invention.